The present invention is directed to a series of substituted pyridine compounds, a method for selectively controlling neurotransmitter release in mammals using these compounds, and pharmaceutical compositions containing these compounds. Preferred compounds are 3xe2x80x2-(5xe2x80x2- and/or 6xe2x80x2-substituted) pyridyl ethers.
Compounds that selectively control chemical synaptic transmission offer therapeutic utility in treating disorders that are associated with dysfunctions in synaptic transmission. This utility may arise from controlling either pre-synaptic or post-synaptic chemical transmission. The control of synaptic chemical transmission is, in turn, a direct result of a modulation of the excitability of the synaptic membrane. Presynaptic control of membrane excitability results from the direct effect an active compound has upon the organelles and enzymes present in the nerve terminal for synthesizing, storing, and releasing the neurotransmitter, as well as the process for active re-uptake. Postsynaptic control of membrane excitability results from the influence an active compound has upon the cytoplasmic organelles that respond to neurotransmitter action.
An explanation of the processes involved in chemical synaptic transmission will help to illustrate more fully the potential applications of the invention. (For a fuller explanation of chemical synaptic transmission refer to Hoffman et al., xe2x80x9cNeuro-transmission: The autonomic and somatic motor nervous systems.xe2x80x9d In: Goodman and Gilman""s, The Pharmacological Basis of Therapeutics, 9th ed., J. G. Hardman, L. E. Limbird, P. B. Molinoff, R. W. Ruddon, and A. Goodman Gilman, eds., Pergamon Press, New York, 1996, pp. 105-139).
Typically, chemical synaptic transmission begins with a stimulus that depolarizes the transmembrane potential of the synaptic junction above the threshold that elicits an all-or-none action potential in a nerve axon. The action potential propagates to the nerve terminal where ion fluxes activate a mobilization process leading to neurotransmitter secretion and xe2x80x9ctransmissionxe2x80x9d to the postsynaptic cell. Those cells which receive communication from the central and peripheral nervous systems in the form of neurotransmitters are referred to as xe2x80x9cexcitable cells.xe2x80x9d Excitable cells are cells such as nerves, smooth muscle cells, cardiac cells and glands. The effect of a neurotransmitter upon an excitable cell may be to cause either an excitatory or an inhibitory postsynaptic potential (EPSP or IPSP, respectively) depending upon the nature of the postsynaptic receptor for the particular neurotransmitter and the extent to which other neurotransmitters are present. Whether a particular neurotransmitter causes excitation or inhibition depends principally on the ionic channels that are opened in the postsynaptic membrane (i.e., in the excitable cell).
EPSPs typically result from a local depolarization of the membrane due to a generalized increased permeability to cations (notably Na+ and K+), whereas IPSPs are the result of stabilization or hyperpolarization of the membrane excitability due to a increase in permeability to primarily smaller ions (including K+ and Clxe2x88x92). For example, the neurotransmitter acetylcholine excites at skeletal muscle junctions by opening permeability channels for Na+ and K+. At other synapses, such as cardiac cells, acetylcholine can be inhibitory, primarily resulting from an increase in K+ conductance.
The biological effects of the compounds of the present invention result from modulation of a particular subtype of acetylcholine receptor. It is, therefore, important to understand the differences between two receptor subtypes. The two distinct subfamilies of acetylcholine receptors are defined as nicotinic acetylcholine receptors and muscarinic acetylcholine receptors. (See Goodman and Gilman""s, The Pharmacological Basis of Therapeutics, op. cit.).
The responses of these receptor subtypes are mediated by two entirely different classes of second messenger systems. When the nicotinic acetylcholine receptor is activated, the response is an increased flux of specific extracellular ions (e.g. Na+, K+ and Ca++) through the neuronal membrane. In contrast, muscarinic acetylcholine receptor activation leads to changes in intracellular systems that contain complex molecules such as G-proteins and inositol phosphates. Thus, the biological consequences of nicotinic acetylcholine receptor activation are distinct from those of muscarinic receptor activation. In an analogous manner, inhibition of nicotinic acetylcholine receptors results in still other biological effects, which are distinct and different from those arising from muscarinic receptor inhibition.
As indicated above, the two principal sites to which drug compounds that affect chemical synaptic transmission may be directed are the presynaptic membrane and the post-synaptic membrane. Actions of drugs directed to the presynaptic site may be mediated through presynaptic receptors that respond to the neurotransmitter which the same secreting structure has released (i.e., through an autoreceptor), or through a presynaptic receptor that responds to another neurotransmitter (i.e., through a heteroreceptor). Actions of drugs directed to the postsynaptic membrane mimic the action of the endogenous neurotransmitter or inhibit the interaction of the endogenous neurotransmitter with a postsynaptic receptor.
Classic examples of drugs that modulate postsynaptic membrane excitability are the neuromuscular blocking agents which interact with nicotinic acetylcholine-gated channel receptors on skeletal muscle, for example, competitive (stabilizing) agents, such as curare, or depolarizing agents, such as succinylcholine.
In the central nervous system, postsynaptic cells can have many neurotransmitters impinging upon them. This makes it difficult to know the precise net balance of chemical synaptic transmission required to control a given cell. Nonetheless, by designing compounds that selectively affect only one pre- or postsynaptic receptor, it is possible to modulate the net balance of all the other inputs. Obviously, the more that is understood about chemical synaptic transmission in CNS disorders, the easier it would be to design drugs to treat such disorders.
Knowing how specific neurotransmitters act in the CNS allows one to predict the disorders that may be treatable with certain CNS-active drugs. For example, dopamine is widely recognized as an important neurotransmitter in the central nervous systems in humans and animals. Many aspects of the pharmacology of dopamine have been reviewed by Roth and Elsworth, xe2x80x9cBiochemical Pharmacology of Midbrain Dopamine Neuronsxe2x80x9d, In: Psychopharmacology: The Fourth Generation of Progress, F. E. Bloom and D. J. Kupfer, Eds., Raven Press, NY, 1995, pp 227-243). Patients with Parkinson""s disease have a primary loss of dopamine containing neurons of the nigrostriatal pathway, which results in profound loss of motor control. Therapeutic strategies to replace the dopamine deficiency with dopamine mimetics, as well as administering pharmacologic agents that modify dopamine release and other neurotransmitters have been found to have therapeutic benefit (xe2x80x9cParkinson""s Diseasexe2x80x9d, In: Psychopharmacology: The Fourth Generation of Progress, op. cit., pp 1479-1484).
New and selective neurotransmitter controlling agents are still being sought, in the hope that one or more will be useful in important, but as yet poorly controlled, disease states or behavior models. For example, dementia, such as is seen with Alzheimer""s disease or Parkinsonism, remains largely untreatable. Symptoms of chronic alcoholism and nicotine withdrawal involve aspects of the central nervous system, as does the behavioral disorder Attention-Deficit Disorder (ADD). Specific agents for the treatment of these and related disorders are few in number or non-existent.
A more complete discussion of the possible utility as CNS-active agents of compounds with activity as cholinergic ligands selective for neuronal nicotinic receptors, (i.e., for controlling chemical synaptic transmission) may be found in U.S. Pat. No. 5,472,958, to Gunn et al., issued Dec. 5, 1995, which is incorporated herein by reference.
Existing acetylcholine agonists are therapeutically suboptimal in treating the conditions discussed above. For example, such compounds have unfavorable pharmacokinetics (e.g., arecoline and nicotine), poor potency and lack of selectivity (e.g., nicotine), poor CNS penetration (e.g., carbachol) or poor oral bioavailability (e.g., nicotine). In addition, other agents have many unwanted central agonist actions, including hypothermia, hypolocomotion and tremor and peripheral side effects, including miosis, lachrymation, defecation and tachycardia (Benowitz et al., in: Nicotine Psychopharmacology, S. Wonnacott, M. A. H. Russell, and I. P. Stolerman, eds., Oxford University Press, Oxford, 1990, pp. 112-157; and M. Davidson, et al., in Current Research in Alzheimer Therapy, E. Giacobini and R. Becker, ed.; Taylor and Francis: New York, 1988; pp 333-336).
Williams et al. reports the use of cholinergic channel modulators to treat Parkinson""s and Alzheimer""s Diseases. M. Williams et al., xe2x80x9cBeyond the Tobacco Debate: Dissecting Out the Therapeutic Potential of Nicotinexe2x80x9d, Exp. Opin. Invest. Drugs 5, pp. 1035-1045 (1996). Salin-Pascual et al. reports short-term improvement of non-smoking patients suffering from depression by treatment with nicotine patches. R. J. Salin-Pascual et al., xe2x80x9cAntidepressant Effect of Transdernal Nicotine Patches in Non-Smoking Patients with Major Depressionxe2x80x9d, J. Clin. Psychiatry, v. 57, pp. 387-389 (1996).
Ethers which are useful as antagonists of specific 5-hydroxy tryptamine (5-HT) receptors are disclosed in GB 2 208 510A; U.S. Pat. No. 4,929,625; U.S. Pat. No. 5,082,843 and U.S. Pat. No. 4,997,839. However, these references disclose a 2-pyridyl moiety linked by oxygen to a saturated azabicyclic ring such as quinuclidyl or tropanyl.
Analgesic pyridine-2-ethers are also disclosed in U.S. Pat. Nos. 4,946,836 and 4,643,995.
In these references, a 2-pyridyl moiety is linked to a nitrogen-containing cycloaliphatic ring through an xe2x80x94Oxe2x80x94(CH2)nxe2x80x94 linkage.
3-Pyridyloxymethyl heterocyclic ether compounds useful in controlling chemical synaptic transmission are disclosed in U.S. Pat. No. 5,629,325; wherein a 3-pyridyl moiety is linked to a nitrogen-containing cycloaliphatic ring through an xe2x80x94Oxe2x80x94CH2xe2x80x94 linkage. PCT Patent Application WO 94/08992 discloses various 3-pyridyloxy-heterocyclic compounds that are either unsubstituted or mono-substituted on the pyndine rings with groups such as Br, Cl, F, hydroxyl, C1-C3 alkyl or C1-C3 alkoxy, such compounds also described as having utility in enhancing cognitive function.
1,3-disubstituted pyrrolidines which have pharmacological action on the central nervous system wherein the pyrrolidine nitrogen is substituted by an xe2x80x94(CH2)nxe2x80x94B group, and ether-linked to a substituted pyridyl, among others are disclosed in U.S. Pat. No. 5,037,841.
Cyclic amine compounds effective against senile dementia wherein the ring is ether-linked to a substituted 3-pyridyl among others are disclosed in European Patent Application No. 0 673 927 A1.
Aza ring ether derivatives and their use as nicotinic ACH receptor modulators are disclosed in WO 99/24422.
U.S. Pat. No. 4,206,117 discloses 3-pyridyl aminoalkyl ether derivatives.
U.S. Pat. No. 5,852,041 discloses a class of pyridine compounds which are modulators of acetylcholine receptors.
However, there is still a need for improved compounds for controlling chemical synaptic transmission.
It is therefore an object of this invention to provide novel substituted pyridine compounds. It is a further object of this invention to provide such compounds which selectively control neurotransmitter release.
The present invention is directed to a series of substituted pyridine compounds, a method for selectively controlling neurotransmitter release in mammals using these compounds, and pharmaceutical compositions including these compounds. More particularly, the present invention is directed to compounds of the formula I 
wherein n is an integer of 1 to 4;
R1 and R2 are independently selected from the group consisting of hydrogen, lower alkyl, alkenyl, alkynyl, aralkyl and cyanomethyl;
R3, at each occurrence, is selected from the group consisting of hydrogen, haloalkyl and lower alkyl;
R4, at each occurrence, is independently selected from the group consisting of hydrogen, hydroxyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, alkenoxy, alkynoxy, thioalkoxy, aliphatic acyl, xe2x80x94CF3, nitro, cyano, xe2x80x94N(C1-C3 alkyl)-C(O)(C1-C3 alkyl), xe2x80x94C1-C3 alkylamino, alkenylamino, alkynylamino, di(C1-C3 alkyl)amino, amino, halogen, xe2x80x94C(O)Oxe2x80x94(C1-C3 alkyl), xe2x80x94C(O)NHxe2x80x94(C1-C3 alkyl), aliphatic acyl, xe2x80x94CHxe2x95x90NOH, xe2x80x94PO3H2, xe2x80x94OPO3H2, heterocyclylalkyl, xe2x80x94C(O)N(C1-C3 alkyl)2, haloalkyl, alkoxylcarbonyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, heterocyclyl, heterocycloyl, alkylaryl, aralkyl, aralkenyl, alkylheterocyclyl, sulfonyl, sulfonamido, carbamate, aryloxyalkyl, carboxyl and xe2x80x94C(O)NH(benzyl);
R5 is selected from the group consisting of hydrogen, halogen, lower alkyl, nitro, lower alkylamino and lower alkoxy;
R6 is selected from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, alkenoxy, alkynoxy, thioalkoxy, aliphatic acyl, xe2x80x94CF3, nitro, amino, cyano, xe2x80x94N(C1-C3 alkyl)-C(O)(C1-C3 alkyl), xe2x80x94C1-C3 alkylamino, alkenylamino, alkynylamino, di(C1-C3 alkyl)amino, xe2x80x94CHxe2x95x90NOH, xe2x80x94C(O)Oxe2x80x94(C1-C3 alkyl), xe2x80x94C(O)NHxe2x80x94(C1-C3 alkyl), xe2x80x94C(O)N(C1-C3 alkyl)2, haloalkyl, alkoxylcarbonyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, heterocyclyl, heterocycloyl, alkylaryl, aralkyl, aralkenyl, alkylheterocyclyl, sulfonyl, sulfonamido, carbamate, aliphatic acyl, xe2x80x94CHxe2x95x90NOH, xe2x80x94PO3H2, xe2x80x94OPO3H2, heterocyclylalkyl, aryloxyalkyl, carboxyl and xe2x80x94C(O)NH(benzyl); and
A is selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(R1)xe2x80x94, xe2x80x94SO2N(R1)xe2x80x94 and xe2x80x94NR1SO2xe2x80x94;
wherein R1, R2, R3, R4, R5 and R6 are unsubstituted or substituted with at least one electron donating or electron withdrawing group;
and pharmaceutically acceptable salts thereof; with the proviso that when Axe2x95x90O, at least one of R5 or R6 is halogen; and with the further proviso that when R3 and R4 are attached to a carbon which is alpha to a heteroatom, R4 is not halogen, hydroxyl or amino.
Presently preferred compounds are of formula II shown below: 
wherein n is an integer of 1 to 4;
R1 and R2 are independently selected from the group consisting of hydrogen, lower alkyl, alkenyl, alkynyl, aralkyl and cyanomethyl;
R3, at each occurrence, is selected from the group consisting of hydrogen, haloalkyl and lower alkyl;
R4, at each occurrence, is independently selected from the group consisting of hydrogen, hydroxyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, alkenoxy, alkynoxy, thioalkoxy, aliphatic acyl, xe2x80x94CF3, nitro, cyano, xe2x80x94N(C1-C3 alkyl)-C(O)(C1-C3 alkyl), xe2x80x94C1-C3 alkylamino, alkenylamino, alkynylamino, di(C1-C3 alkyl)amino, amino, halogen, xe2x80x94C(O)Oxe2x80x94(C1-C3 alkyl), xe2x80x94C(O)NHxe2x80x94(C1-C3 alkyl), aliphatic acyl, xe2x80x94CHxe2x95x90NOH, xe2x80x94PO3H2, xe2x80x94OPO3H2, heterocyclylalkyl, xe2x80x94C(O)N(C1-C3 alkyl)2, haloalkyl, alkoxylcarbonyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, heterocyclyl, heterocycloyl, alkylaryl, aralkyl, aralkenyl, alkylheterocyclyl, sulfonyl, sulfonamido, carbamate, aryloxyalkyl, carboxyl and xe2x80x94C(O)NH(benzyl);
R5 is selected from the group consisting of hydrogen, halogen, lower alkyl, nitro, lower alkylamino and lower alkoxy; and
R6 is selected from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, alkenoxy, alkynoxy, thioalkoxy, aliphatic acyl, xe2x80x94CF3, nitro, amino, cyano, xe2x80x94N(C1-C3 alkyl)-C(O)(C1-C3 alkyl), xe2x80x94C1-C3 alkylamino, alkenylamino, alkynylamino, di(C1-C3 alkyl)amino, xe2x80x94C(O)Oxe2x80x94(C1-C3 alkyl), xe2x80x94C(O)NHxe2x80x94(C1-C3 alkyl), xe2x80x94CHxe2x95x90NOH, xe2x80x94C(O)N(C1-C3 alkyl)2, haloalkyl, alkoxylcarbonyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, heterocyclyl, heterocycloyl, alkylaryl, aralkyl, aralkenyl, alkylheterocyclyl, sulfonyl, sulfonamido, carbamate, aliphatic acyl, xe2x80x94CHxe2x95x90NOH, xe2x80x94PO3H2, xe2x80x94OPO3H2, heterocyclylalkyl, aryloxyalkyl, carboxyl and xe2x80x94C(O)NH(benzyl);
wherein R1, R2, R3, R4, R5 and R6 are unsubstituted or substituted with at least one electron donating or electron withdrawing group;
and pharmaceutically acceptable salts thereof;
with the proviso that when R3 and R4 are attached to a carbon
which is alpha to a heteroatom, R4 is not halogen, hydroxyl or amino;
and with the further proviso that at least one of R5 or R6 is halogen.
Presently preferred are compounds of formula II wherein n=2, R5 is halogen and R6 is selected from the group consisting of hydrogen, lower alkyl and halogen.
Presently most preferred compounds are of formula III shown below: 
wherein n is an integer of 1 to 4;
R1 and R2 are independently selected from the group consisting of hydrogen and lower alkyl;
R3 is selected from the group consisting of hydrogen, haloalkyl and lower alkyl;
R5 is selected from the group consisting of hydrogen, halogen, lower alkyl, nitro, lower alkylamino and lower alkoxy; and
R6 is selected from the group consisting of hydrogen, halogen, hydroxyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, alkenoxy, alkynoxy, thioalkoxy, aliphatic acyl, xe2x80x94CF3, nitro, amino, cyano, xe2x80x94N(C1xe2x80x94C3 alkyl)-C(O)(C1-C3 alkyl), xe2x80x94C1-C3 alkylamino, alkenylamino, alkynylamino, di(C1-C3 alkyl)amino, CHxe2x95x90NOH, xe2x80x94C(O)Oxe2x80x94(C1-C3 alkyl), xe2x80x94C(O)NHxe2x80x94(C1-C3 alkyl), xe2x80x94C(O)N(C1-C3 alkyl)2, haloalkyl, alkoxylcarbonyl, alkoxyalkoxy, aliphatic acyl, xe2x80x94CHxe2x95x90NOH, xe2x80x94PO3H2, xe2x80x94OPO3H2, heterocyclylalkyl, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, heterocyclyl, heterocycloyl, alkylaryl, aralkyl, aralkenyl, alkylheterocyclyl, sulfonyl, sulfonamido, carbamate, aryloxyalkyl, carboxyl and -C(O)NH(benzyl);
wherein R1, R2, R3, R5 and R6 are unsubstituted or substituted with at least one electron donating or electron withdrawing group;
and pharmaceutically acceptable salts thereof;
with the proviso that at least one of R5 or R6 is halogen.
Presently preferred compounds of formula III have R5 and R6 each independently selected from the group consisting of lower alkyl, xe2x80x94F, xe2x80x94Cl and xe2x80x94Br; n=1 or 2 and R3 as lower alkyl or haloalkyl.
Presently preferred compounds include 5-[(S)-2-amino-1-propyloxy]-2-chloro pyridine, 5-[(S)-2-methylamino-1-propyloxy]-2-chloro pyridine, 5-[(S)-2-amino-1-propyloxy]-2-fluoro pyridine, 5-[(S)-2-methylamino-1-propyloxy]-2-fluoro pyridine, 5-[(S)-2-methylamino-1-propyloxy]-2-chloro-3-bromo pyridine, 5-[(S)-2-methylamino-1-propyloxy]-2-chloro-3-methyl pyridine and pharmaceutically acceptable salts thereof including, but not limited to p-toluene sulfonic acid.
The term xe2x80x9calkylxe2x80x9d as used herein alone or in combination refers to C1-C12 straight or branched, substituted or unsubstituted saturated chain radicals derived from saturated hydrocarbons by the removal of one hydrogen atom, unless the term alkyl is preceded by a Cx-Cy designation. Representative examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl among others.
The term xe2x80x9calkenylxe2x80x9d, alone or in combination, refers to a substituted or unsubstituted straight-chain or substituted or unsubstituted branched-chain alkenyl radical containing from 2 to 10 carbon atoms. Examples of such radicals include, but are not limited to, ethenyl, E- and Z-pentenyl, decenyl and the like.
The term xe2x80x9calkynylxe2x80x9d, alone or in combination, refers to a substituted or unsubstituted straight or substituted or unsubstituted branched chain alkynyl radical containing from 2 to 10 carbon atoms. Examples of such radicals include, but are not limited to ethynyl, propynyl, propargyl, butynyl, hexynyl, decynyl and the like.
The term xe2x80x9clowerxe2x80x9d modifying xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d, xe2x80x9calkynylxe2x80x9d or xe2x80x9calkoxyxe2x80x9d refers to a C1-C6 unit for a particular functionality. For example lower alkyl means C1-C6 alkyl.
The term xe2x80x9caliphatic acylxe2x80x9d alone or in combination, refers to radicals of formula alkyl-C(O)xe2x80x94, alkenyl-C(O)xe2x80x94 and alkynyl-C(O)xe2x80x94 derived from an alkane-, alkene- or alkyncarboxylic acid, wherein the terms xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d are as defined above. Examples of such aliphatic acyl radicals include, but are not limited to, acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, acryloyl, crotyl, propiolyl and methylpropiolyl, among others.
The term xe2x80x9ccycloalkylxe2x80x9d as used herein refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings, including, but not limited to cyclopropyl, cyclopentyl, cyclohexyl, norbomyl, and adamantyl among others. Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. xe2x80x9cCycloalkylxe2x80x9d includes cis or trans forms. Furthermore, the substituents may either be in endo or exo positions in the bridged bicyclic systems.
The term xe2x80x9ccycloalkenylxe2x80x9d as used herein alone or in combination refers to a cyclic carbocycle containing from 4 to 8 carbon atoms and one or more double bonds. Examples of such cycloalkenyl radicals include, but are not limited to, cyclopentenyl, cyclohexenyl, cyclopentadienyl and the like.
The term xe2x80x9ccycloalkylalkylxe2x80x9d as used herein refers to a cycloalkyl group appended to a lower alkyl radical, including, but not limited to cyclohexylmethyl.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to I, Br, Cl or F.
The term xe2x80x9chaloalkylxe2x80x9d as used herein refers to a lower alkyl radical, to which is appended at least one halogen substituent, for example chloromethyl, fluoroethyl, trifluoromethyl and pentafluoroethyl among others.
The term xe2x80x9calkoxyxe2x80x9d, alone or in combination, refers to an alkyl ether radical, wherein the term xe2x80x9calkylxe2x80x9d is as defined above. Examples of suitable alkyl ether radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
The term xe2x80x9calkenoxyxe2x80x9d, alone or in combination, refers to a radical of formula alkenyl-Oxe2x80x94, provided that the radical is not an enol ether, wherein the term xe2x80x9calkenylxe2x80x9d is as defined above. Examples of suitable alkenoxy radicals include, but are not limited to, allyloxy, E- and Z-3-methyl-2-propenoxy and the like.
The term xe2x80x9calkynoxyxe2x80x9d, alone or in combination, refers to a radical of formula alkynyl-Oxe2x80x94, provided that the radical is not an -ynol ether. Examples of suitable alkynoxy radicals include, but are not limited to, propargyloxy, 2-butynyloxy and the like.
The term xe2x80x9ccarboxylxe2x80x9d as used herein refers to a carboxylic acid radical, xe2x80x94C(O)OH.
The term xe2x80x9cthioalkoxyxe2x80x9d, refers to a thioether radical of formula alkyl-Sxe2x80x94, wherein xe2x80x9calkylxe2x80x9d is as defined above.
The term xe2x80x9ccarboxaldehydexe2x80x9d as used herein refers to xe2x80x94C(O)R wherein R is hydrogen.
The term xe2x80x9ccarboxamidexe2x80x9d as used herein refers to xe2x80x94C(O)NRaRb wherein Ra and Rb are each independently hydrogen, alkyl or any other suitable substituent.
The term xe2x80x9calkoxyalkoxyxe2x80x9d as used herein refers to RcOxe2x80x94RdOxe2x80x94 wherein Rc is lower alkyl as defined above and RF is alkylene wherein alkylene is xe2x80x94(CH2)nxe2x80x2xe2x80x94 wherein nxe2x80x2 is an integer from 1 to 6. Representative examples of alkoxyalkoxy groups include methoxymethoxy, ethoxyinethoxy, t-butoxymethoxy among others.
The term xe2x80x9calkylaminoxe2x80x9d as used herein refers to ReNHxe2x80x94 wherein Re is a lower alkyl group, for example, ethylamino, butylamino, among others.
The term xe2x80x9calkenylaminoxe2x80x9d alone or in combination, refers to a radical of formula alkenyl-NHxe2x80x94 or (alkenyl)2Nxe2x80x94, wherein the term xe2x80x9calkenylxe2x80x9d is as defined above, provided that the radical is not an enamine. An example of such alkenylamino radical is the allylamino radical.
The term xe2x80x9calkynylaminoxe2x80x9d, alone or in combination, refers to a radical of formula alkynyl-NHxe2x80x94 or (alkynyl)2Nxe2x80x94 wherein the term xe2x80x9calkynylxe2x80x9d is as defined above, provided that the radical is not an amine. An example of such alkynylamino radicals is the propargyl amino radical.
The term xe2x80x9cdialkylaminoxe2x80x9d as used herein refers to RfRgNxe2x80x94 wherein Rf and Rg are independently selected from lower alkyl, for example diethylamino, and methyl propylamino, among others.
The term xe2x80x9caminoxe2x80x9d as used herein refers to H2Nxe2x80x94.
The term xe2x80x9calkoxycarbonylxe2x80x9d as used herein refers to an alkoxyl group as previously defined appended to the parent molecular moiety through a carbonyl group. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, and isopropoxycarbonyl among others.
The term xe2x80x9carylxe2x80x9d or xe2x80x9caromaticxe2x80x9d as used herein alone or in combination refers to a substituted or unsubstituted carbocyclic aromatic group having about 6 to 12 carbon atoms such as phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl and anthracenyl; or a heterocyclic aromatic group selected from the group consisting of furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, 2,3-dihydrobenzofuranyl, benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxyazinyl, pyrazolo[1,5-c]triazinyl and the like. xe2x80x9cArylalkylxe2x80x9d and xe2x80x9calkylarylxe2x80x9d employ the term xe2x80x9calkylxe2x80x9d as defined above. Rings may be multiply substituted.
The term xe2x80x9caralkylxe2x80x9d, alone or in combination, refers to an aryl substituted alkyl radical, wherein the terms xe2x80x9calkylxe2x80x9d and xe2x80x9carylxe2x80x9d are as defined above. Examples of suitable aralkyl radicals include, but are not limited to, phenylmethyl, phenethyl, phenylhexyl, diphenylmethyl, pyridylmethyl, tetrazolyl methyl, furylmethyl, imidazolyl methyl, indolylmethyl, thienylpropyl and the like.
The term xe2x80x9caralkenylxe2x80x9d, alone or in combination, refers to an aryl substituted alkenyl radical, wherein the terms xe2x80x9carylxe2x80x9d and xe2x80x9calkenylxe2x80x9d are as defined above.
The term xe2x80x9carylaminoxe2x80x9d, alone or in combination, refers to a radical of formula aryl-NHxe2x80x94, wherein xe2x80x9carylxe2x80x9d is as defined above. Examples of arylamino radicals include, but are not limited to, phenylamino(anilido), naphthlamino, 2-, 3-, and 4- pyridylamino and the like.
The term xe2x80x9cbiarylxe2x80x9d, alone or in combination, refers to a radical of formula aryl-aryl, wherein the term xe2x80x9carylxe2x80x9d is as defined above.
The term xe2x80x9cthioarylxe2x80x9d, alone or in combination, refers to a radical of formula aryl-Sxe2x80x94, wherein the term xe2x80x9carylxe2x80x9d is as defined above. An example of a thioaryl radical is the thiophenyl radical.
The term xe2x80x9caroylxe2x80x9d, alone or in combination, refers to a radical of formula aryl-COxe2x80x94, wherein the term xe2x80x9carylxe2x80x9d is as defined above. Examples of suitable aromatic acyl radicals include, but are not limited to, benzoyl, 4-halobenzoyl, 4-carboxybenzoyl, naphthoyl, pyridylcarbonyl and the like.
The term xe2x80x9cheterocyclylxe2x80x9d, alone or in combination, refers to a non-aromatic 3- to 10-membered ring containing at least one endocyclic N, O, or S atom. The heterocycle may be optionally aryl-fused. The heterocycle may also optionally be substituted with at least one substituent which is independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, carboxyalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl among others.
The term xe2x80x9calkylheterocyclylxe2x80x9d as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a heterocyclyl group.
The term xe2x80x9cheterocyclylalkylxe2x80x9d as used herein refers to a heterocyclyl group as previously defined appended to the parent molecular moiety through an alkyl group.
The term xe2x80x9caminalxe2x80x9d as used herein refers to the structure RhC(NRiRj)(NRkRl)xe2x80x94 wherein Rh, Ri, Rj, Rk and Rl are each independently hydrogen, alkyl or any other suitable substituent.
Use of the above terms is meant to encompass substituted and unsubstituted moieties. Substitution may be by one or more groups such as alcohols, ethers, esters, amides, sulfones, sulfides, hydroxyl, nitro, cyano, carboxy, amines, heteroatoms, lower alkyl, lower alkoxy, lower alkoxycarbonyl, alkoxyalkoxy, acyloxy, halogens, trifluoromethoxy, trifluoromethyl, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, alkylheterocyclyl, heterocyclylalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl or any of the substituents of the preceding paragraphs or any of those substituents either attached directly or by suitable linkers. The linkers are typically short chains of 1-3 atoms containing any combination of xe2x80x94Cxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)Oxe2x80x94 or xe2x80x94S(O)Oxe2x80x94. Rings may be substituted multiple times.
The terms xe2x80x9celectron-withdrawingxe2x80x9d or xe2x80x9celectron-donatingxe2x80x9d refer to the ability of a substituent to withdraw or donate electrons relative to that of hydrogen if hydrogen occupied the same position in the molecule. These terms are well-understood by one skilled in the art and are discussed in Advanced Organic Chemistry by J. March, 1985, pp. 16-18, incorporated herein by reference. Electron withdrawing groups include halo, nitro, carboxyl, lower alkenyl, lower alkynyl, carboxaldehyde, carboxyamido, aryl, quaternary ammonium, trifluoromethyl, and aryl lower alkanoyl among others. Electron donating groups include such groups as hydroxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, aryloxy, mercapto, lower alkylthio, lower alkylmercapto, and disulfide among others. One skilled in the art will appreciate that the aforesaid substituents may have electron donating or electron withdrawing properties under different chemical conditions. Moreover, the present invention contemplates any combination of substituents selected from the above-identified groups.
The most preferred electron donating or electron withdrawing substituents are halo, nitro, alkanoyl, carboxaldehyde, arylalkanoyl, aryloxy, carboxyl, carboxamide, cyano, sulfonyl, sulfoxide, heterocyclyl, guanidine, quaternary ammonium, lower alkenyl, lower alkynyl, sulfonium salts, hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, amine lower alkyl mercapto, mercaptoalkyl, alkylthio and alkyldithio.
As used herein, the term xe2x80x9ccompositionxe2x80x9d is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from a combination of the specified ingredients in the specified amounts.
The term xe2x80x9cheteroatomxe2x80x9d as used herein encompasses nitrogen, sulfur and oxygen.
The term xe2x80x9calphaxe2x80x9d as used herein indicates the position immediately adjacent to the position described.
Abbreviations which have been used in the reaction schemes and the examples that follow have the following meanings: BOC for t-butyloxycarbonyl, Et2O for diethyl ether, EtOAc for ethyl acetate, MeOH for methanol, EDC for ethylene dichloride, FMOC for 9-fluorenyl methoxy carbonyl, DMF for dimethylformamide, LAH for lithium aluminum hydride, DEAD for diethylazodicarboxylate and TFA for trifluoroacetic acid.
The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The phrase xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d means those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well-known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: p. 1 et seq. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable organic acid. Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quatemized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which can be required. Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention can be varied so as to obtain an amount of the active compound(s) which is effective to achieve the desired therapeutic response for a particular patient, compositions and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
When used in the above or other treatments, a therapeutically effective amount of one of the compounds of the present invention can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester or prodrug form. Alternatively, the compound can be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable excipients. The phrase xe2x80x9ctherapeutically effective amountxe2x80x9d of the compound of the invention means a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
The total daily dose of the compounds of this invention administered to a human or lower animal may range from about 0.0001 to about 1000 mg/kg/day. For purposes of oral administration, more preferable doses can be in the range of from about 0.001 to about 5 mg/kg/day. If desired, the effective daily dose can be divided into multiple doses for purposes of administration; consequently, single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
The present invention also provides pharmaceutical compositions that comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions can be specially formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.
The pharmaceutical compositions of this invention can be administered to humans and other mammals orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray. The term xe2x80x9cparenterally,xe2x80x9d as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrastemal, subcutaneous and intraarticular injection and infusion.
Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), vegetable oils (such as olive oil), injectable organic esters (such as ethyl oleate) and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.
Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients and the like. The preferred lipids are natural and synthetic phospholipids and phosphatidyl cholines (lecithins) used separately or together.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
The term xe2x80x9cpharmaceutically acceptable prodrugsxe2x80x9d as used herein represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. Prodrugs of the present invention may be rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, xe2x80x9cPro-drugs as Novel Delivery Systemsxe2x80x9d, V. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987), hereby incorporated by reference.
The present invention contemplates both synthetic compounds of formulae I-III of the present invention, as well as compounds formed by in vivo conversion to compounds of the present invention.
Compounds of the present invention may exist as stereoisomers wherein asymmetric or chiral centers are present. These stereoisomers are xe2x80x9cRxe2x80x9d or xe2x80x9cSxe2x80x9d depending on the configuration of substituents around the chiral carbon atom. The present invention contemplates various stereoisomers and mixtures thereof. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of compounds of the present invention may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
The compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms, such as hemi-hydrates. In general, the solvated forms, with pharmaceutically acceptable solvents such as water and ethanol among others are equivalent to the unsolvated forms for the purposes of the invention.
The present compounds may have activity against disorders which are mediated through the central nervous system. The following references describe various disorders affected by nicotinic acetylcholine receptors: 1) Williams, M.; Arneric, S. P.: xe2x80x9cBeyond the Tobacco Debate: dissecting out the therapeutic potential of nicotinexe2x80x9d Exp. Opin. Invest. Drugs (1996) 5 (8) pp. 1035-1045; 2) Arneric, S. P.; Sullivan, J. P.; Williams, W.: xe2x80x9cNeuronal nicotinic acetylcholine receptors. Novel targets for central nervous system theraputics.xe2x80x9d In: Psychopharmacology: The Fourth Generation of Progress. Bloom FE, Kupfer DJ (Eds.), Raven Press, New York (1995): 95-109; 3) Arneric, S. P.; Holladay, M. W.; Sullivan, J. P.: xe2x80x9cCholinergic channel modulators as a novel therapeutic strategy for Alzheimer""s disease.xe2x80x9d Exp. Opin. Invest. Drugs (1996) 5 (1): 79-100; 4) Lindstrom, J.: xe2x80x9cNicotinic Acetylchloline Receptors in Health and Disease.xe2x80x9d Molecular Neurobiology (1997) 15: pp. 193-222; and 5) Lloyd, G K; Menzaghi, F; Bontempi B; Suto, C; Siegel, R; Akong, M; Stauderman, K; Velicelebi, G; Johnson, E; Harpold, M M; Rao, T S; Sacaan, A I; Chavez-Noriega, L E; Washburn, M S; Vernier, J M; Cosford, N D P; McDonald, L A: xe2x80x9cThe potential of subtype-selective neuronal nicotinic acetylcholine receptor agonists as therapeutic agents.xe2x80x9d Life Sciences (1998) 62 (17/18):pp. 1601-1606. These disorders include, but are not limited to the following: pain (references 1 and 2), Alzheimer""s disease (references 1-5), Parkinson""s disease (references 1, 4 and 5), memory disfunction, Tourette""s syndrome (references 1, 2 and 4), sleep disorders (reference 1), attention deficit hyperactivity disorder (references 1 and 3), neurodegeneration, inflammation, neuroprotection (references 2 and 3), amyotrophic atral sclerosis, anxiety (references 1, 2 and 3), depression (reference 2), mania, schizophrenia (references 1, 2 and 4), anorexia and other eating disorders, AIDS-induced dementia, epilepsy (references 1,2 and 4), urinary incontinence (reference 1), Crohn""s disease, migraines, PMS, erectile disfunction, substance abuse, smoking cessation (references 1 and 2) and inflammatory bowel syndrome (references 1 and 4) among others.
The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes which illustrate the methods by which the compounds of the invention may be prepared.
The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes which illustrate the methods by which the compounds of the invention may be prepared. As indicated in Scheme 1, a suitably N-protected amino acid may be converted to the corresponding alcohol, by the action of one of several appropriate reducing agents, including for example BH3xe2x80x94THF, BH3xe2x80x94SMe2, DiBAlxe2x80x94H, LiAlH4, and the like. The t-butoxycarbonyl (Boc) group is illustrated, but other standard N-protecting groups can also be used, including for example benzyloxycarbonyl, benzyl, toluenesulfonyl, FMOC, and phthalimido among others. The starting amino acids are chiral, and generally available from commercial sources in either R or S-configuration, as well as in the racemic modification. Since the reduction and subsequent transformations can be achieved while maintaining optical purity, the methods outlined below provide access to individual enantiomers, as well as racemates of the final compounds. 
Formation of the pyridyl ether may be accomplished in two distinct ways. One construct involves activation of the hydroxyl group of the amino alcohol and its subsequent displacement by a substituted hydroypyridine. Thus, as illustrated in Scheme 1, conversion of the alcohol to a good leaving group, such as a sulfonate ester (tosylate, mesylate, etc.) or halides provides suitable activation so that reaction with an hydroxypyridine under basic conditions will produce the ether. Alternatively, activation of the alcohol with triphenylphosphine and a dialkyl azodicarboxylate allows ether formation under neutral conditions.
An alternate mode for pyridyl ether formation is illustrated in Scheme 2.
In this process, the alcohol is engaged in aromatic substitution of a substituted pyridine. Suitable leaving groups on the pyridine include halide, nitro, and trifluoromethanesulfonate. In favorable cases, substitution can be achieved by reaction of the alkoxide, formed from the alcohol by action of sodium or potassium hydride, directly with the substituted pyridine. For less-reactive pyridines, a suitable transition metal catalyst (e.g, palladium or copper complexes) may be used to facilitate the displacement.
Scheme 3 illustrates that deprotection of the amine may be accomplished in conjunction with alkylation to provide a primary, secondary, or tertiary amine, as desired. Thus, alkylation of the Boc-protected amine with a suitable alkyl halide provides for introduction of one alkyl group. Removal of the protecting group under acidic conditions provides the secondary amine, which can be alkylated again with the same or a different alkyl group. Other standard manipulations of the amine also apply, so that amine alkylations can be accomplished via condensation with an aldehyde or ketone with reduction by NaBH3CN, NaBH4, or H2 (reductive amination), or acylation with, e.g., an acyl halide followed by reduction with LiAIH4.
In this manner, the range of nitrogen substituents represented in the invention may be introduced. 
Further elaboration of the pyridine substituents may be accomplished after ether formation as illustrated in Scheme 4. A halide substituent may be activated by palladium catalysis to Cxe2x80x94C bond formation with aryl, vinyl and alkynyl tin of boronate derivatives. Likewise, alkenes can be added via the Heck reaction, and a similar process allows incorporation of a nitrile. The products of these initial transformations may be further elaborated according to standard, well-known methods of organic synthesis to provide further compounds of the invention. Another useful method involves lithiation of the halopyridine with trapping of the organolithium intermediate by a suitable electrophile, for example N,N-dimethylformamide for introduction of the formyl group. This can in turn be elaborated in a variety of ways familiar to one skilled in the art, including reduction and addition of suitable organometallic reagents. 
The following examples are presented to describe the preferred embodiements and utilities of the invention, and are not meant to limit the invention unless otherwise stated in the claims appended hereto.